The invention relates to an improved process for preparing the 2-methyl-2-hydroxypropyl piperazine-1-carboxylate moiety of certain preferred quinazoline derivatives which are useful antihypertensive agents. In general this moiety is a member of a large class of 2-position substituents of quinazoline antihypertensive agents which are described in the following U.S. Pat. Nos.: 3,980,650, 3,935,213, 3,769,286, 3,669,968, 3,663,706, 3,635,979 and 3,511,836. In particular the quinazoline agents possessing this moiety are mentioned in the '286, '968 and '706 patents as being especially interesting because they have a high degree of hypotensive activity.
Known synthetic procedures for forming the preferred quinazoline derivatives such as 2-methyl-2-hydroxypropyl 4-(4-amino-6,7,8-trimethoxyquinazolin-2-yl)piperazine-1-carboxylate or its corresponding 6,7-dimethoxy analog all employ hydration of a methallyl carbonate moiety to form the desired 2-methyl-2-hydroxy-propyl group (U.S. Pat. Nos. 3,663,706 and 3,769,286). Several synthetic variations of this route are described but no matter which is used, the yield of the 2-methyl-2-hydroxypropyl piperazine-1-carboxylate moiety is low owing to competing hydrolysis of the carbamate group during hydration of the methallyl group.
Another method for synthesis of this type of moiety employs the reaction of carbonates with amines to form the corresponding carbamates. The reaction has been extensively studied and the variety of carbonates and amines used is illustrated by the following: J. Katzhendler et. al., J. Chem. Soc., Perkin Trans. 2, 1972, 2019; U.S. Pat. No. 3,703,538; M. Baizer et. al., J. Org. Chem., 22, 1706 (1957); French Pat. No. 1,096,204 and French Patent of Addition 62617.
According to the carbonate method, isobutylene carbonate is required for the synthesis of the 2-methyl-2-hydroxypropyl piperazine-1-carboxylate side chain. However, its reaction with amine is capable of producing two isomers. Hence it would not be expected to provide an effective route to the desired antihypertensive agents because of significant contamination with the unwanted structural isomer.
A confusing story is presented by the prior art. According to the French addition patent, the reaction of a similar asymmetric carbonate, propylene carbonate, with amines in water produces the 2-hydroxyprop-1-yl carbamate compound rather than the 1-hydroxyprop-2-yl structural isomer. These results are refuted by Beizer and Katzhendler who show that mixtures of the two possible isomers are obtained.
It is thus surprising to discover that the desired 2-methyl-2-hydroxypropyl piperazine-1-carboxylate compound is produced essentially free of the undesired structural isomer when isobutylene carbonate is reacted with the appropriate piperazine compound according to the processes of the present invention.